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Title page for ETD etd-04162012-131238

Type of Document

Dissertation

Author

Abreu, Maria Mercedes

Author's Email Address

mariamercedesabreu@gmail.com

URN

etd-04162012-131238

Title

C/EBPbeta3 (LIP) induces cell death in breast cancer cells.

Degree

PhD

Department

Cancer Biology

Advisory Committee

Advisor Name

Title

Andries Zijlstra

Committee Chair

Barbara FIngleton

Committee Member

Linda Sealy

Committee Member

Vito Quaranta

Committee Member

Keywords

C/EBPbeta

breast cancer

cell death

autophagy

Date of Defense

2012-04-06

Availability

unrestricted

Abstract

C/EBPbeta is a member of a family of basic-leucine zipper transcription factors. It has been shown to be a key regulator of growth and differentiation in the mammary gland. There are three different protein isoforms of C/EBPbeta. C/EBPbeta-1 and -2 are transactivators, and differ by just 23 N-terminal amino acids present in beta-1 only. C/EBPbeta-3 (LIP) lacks the transactivation domain and represses transcription. Overexpression of LIP is incompatible with cell proliferation and induces cell death in breast cancer cell lines. LIP expression stimulates autophagy, an evolutionarily conserved cellular process responsible for self-cannabalization through a lysosomal degradation pathway. Interestingly, I find that LIP expression not only leads to self-cannibalization in the MDA-MB-468 breast cancer cell line, but cell cycle profiling reveals a dramatic increase in DNA content in LIP expressing cells. I present data that the induction of autophagy appears to accompany or possibly follow the cannibalization or engulfment of neighboring cells by the LIP expressing cells. LIP expression was found to upregulate HSPA1A transcripts and concomitantly leads to increases in HSP70 protein levels in exosomes. Exosomes are 30- to 100-nm lipid bilayer vesicles that function to promote intercellular communication. LIP-derived exosomes appear to play a role in marking target cells for engulfment. Finally, I present data to show that LIP-induced cell engulfment may play a physiological role during involution of the mammary gland.